Separation of the receptor for thyrotropin
from thyroid cells may be important in Graves' hyperthyroidism
(November 2002)
The background of
the study. The cause of hyperthyroidism in patients with
Graves' disease is stimulation of thyroid hormone production by
antibodies (thyrotropin [TSH] receptor-stimulating antibodies [TSHR-SAb])
that bind to and activate receptors for TSH, just as does TSH. The
receptors are long molecules that extend from outside thyroid cells
through their outer membrane to the inside (cytoplasm) of the cells.
TSHR-SAb and TSH bind primarily to the end of the receptor that
lies outside the cells, and much of this end can be cleaved from
the remainder and released into the extracellular fluid that surrounds
the cells. This study was done to determine the reactivity of different
parts of the receptor with TSH and TSHR-SAb.
How the study was done. Intact TSH
receptors or the end segment of the receptor anchored to the cell
membrane were expressed in hamster ovary cells. The cells were incubated
with serum samples from 20 patients with Graves' hyperthyroidism
that contained TSHR-SAb, from 7 patients with hypothyroidism that
contained TSH receptor-blocking antibodies (TSH-BAb), and from 9
normal subjects who had neither type of antibody. The cells were
then stained to determine if any TSHR-SAb was bound to them.
The results of the study. Serum
from 17 of the 20 patients with Graves' hyperthyroidism bound to
the cells containing the end segment of the TSH receptor better
than to the cells containing intact receptors. In contrast, serum
from patients with hypothyroidism bound equally well to both types
of cell. Serum from normal subjects did not bind to either type
of cell. Preincubation of cleaved end segments with serum from patients
with Graves' hyperthyroidism abolished serum binding to the cells.
The conclusions of the study. TSHR-SAb
in serum from patients with Graves' hyperthyroidism bind preferentially
to the end-and most exposed-segment of the TSH receptor, and the
binding is blocked by preincubation with cleaved end segments. The
natural release of end segments into extracellular fluid may be
an important source of antigen for production of TSHR-SAb.
The original article. Chazenbalk
GD, Pichurin P, Chen CR, Latrofa F, Johnstone AP, McLachlan SM,
Rapoport B. Thyroid-stimulating autoantibodies in Graves' disease
preferentially recognize the free A subunit, not the thyrotropin
holoreceptor. J Clin Invest 2002;110:209-17.
|
